In Vitro Drug Release

Kinetic Models

PhD Scholar: Kalsoom Saleem

CMS# 389697
Table of Contents
1. Introduction
2. Mathematical Models of Drug
Release/Model Dependent
Approaches
2.1. Zero-order Kinetics
2.2. First-order Kinetics
2.3. Higuchi Model
2.4. Hixson–Crowell Model
2.5. Ritger–Peppas and Korsmeyer–Peppas
Model (Power Law)
2.6. Brazel and Peppas model
2.7. Weibull model
3. Model Independent Approaches
4. Selection of Best Model
5. Case study
6. Conclusion
7. References
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1.
Introduction
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 1. Introduction

▰ Definition: Drug release refers to the process in which drug solutes migrate from the
initial position in the polymeric system to the polymer’s outer surface and then to the
release medium.

▰ Definition: Release kinetic studies are defined as in vitro drug release profile study
which are done to analyze the quantitative and qualitative changes in formulations that
may affect drug release and its activity.

▰ Significance: It constitutes a prerequisite to absorption of the therapeutic agent, the rate

and extent of active/drug availability to the body. 4
 1. Introduction

▰ Release patterns: The release patterns comprise the zero- and first-order rate. In
addition, there are those that provide an initial rapid dose (burst release), followed by
zero- or first-order release of the sustained component i.e. controlled dosage forms.

▰ Aim: Therefore, controlled release dosage forms enable pharmacists and engineers to
work together with the aim of designing controlled drug delivery systems. To provide
particular, predetermined release profiles, it is necessary to know the exact mass
transport mechanisms involved in drug release, and to predict quantitatively the
resulting drug release kinetics. 5
1. Introduction

▰ Objective: It is possible to acquire a mathematical equation that describes

the dependence of release in function of time, the use of which could be
helpful in predicting the release kinetics before the release systems are
realized.

▰ Outcome: Therefore, many mathematical models were made to design a

number of simple and complex drug delivery systems and devices and to
predict the overall release behavior1.
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2.
Mathematical Models of
Drug Release/Model
Dependent Approaches
7
2. Mathematical Models of Drug Release

▰ The mathematical models are used to predict the followings2:

1. Design pharmaceutical formulations, evaluate drug release processes* in vitro and in
vivo and, in general, come up with the optimal design for new systems.
2. Measurement of physical parameters (e.g. drug diffusion coefficient) and route to
model fitting on experimental release data.
3. The amount and type of active agent, polymer and adjuvants as well as the size and
shape of the system designed to achieve a certain drug release profile.
4. Quantitative interpretation of the values obtained from a dissolution or drug release
assay i.e. the release mechanism of the encapsulated molecule(s)/drug(s) (release
kinetics).
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5. Reduce the necessity of biostudies**
2. Mathematical Models of Drug Release
▰ Drug Release Systems/Processes2:
▻ 1. Drug diffusion from the non-degraded polymer (diffusion-controlled system).
▻ 2. Enhanced drug diffusion due to polymer swelling (swelling-controlled system).
▻ 3. Drug release due to polymer degradation and erosion (erosion-controlled system).

▰ In all three systems, diffusion is always involved. Hence, Fick’s laws of diffusion
provide description of solute transport from polymeric matrices.
▻ Fick’s First Law: A solute moves from a region of high concentration to a region of low concentration
across a concentration gradient.
▻ Fick’s Second Law: The effect of diffusion on change in concentration with time at a definite location.
▰ When a diffusion process does not follow Fick's laws, it is referred to as 
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non-Fickian.
 2.1 Zero-order Kinetics3
▰ Equation: Ct= C0 + K0t
▻ Ct = amount of drug released during the time t,
▻ C0 = initial concentration of drug released,
▻ K0 is the zero-order rate constant.
▰ Drug Release Rate: Independent of concentration
▰ For zero-order kinetics, the release of an active agent is only a function of time and the
process takes place at a constant rate independent of active agent concentration
▰ Graphical Representation: %C vs t, straight line

▰ Examples: Oral osmotic pressure release, Oral control release, Suspensions, Implantable
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depot, Transdermals, Matrix tablets
2.1 Zero-order Kinetics3

(C)

K=slope

(t)
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 2.2 First-order Kinetics4
▰ Equation: logQ= logQ0+K.t/2.303
▻ Q = amount of drug released on time t,
▻ Q0 is the initial amount of drug,
▻ K = first-order rate constant
▰ Drug Release Rate: Dependent on concentration
▰ the amount of drug released is proportional to the amount of remaining drug in the
matrix i.e. The greater the drug concentration, the greater the drug release and vice
versa . Thus, the amount of active released tends to decrease in function of time.
▰ Graphical Representation: log of % drug released vs t

▰ Examples: Solutions, Matrix diffusion and dissolution controlled release, Sustained

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release
2.2 First-order Kinetics4

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 2.3 Higuchi Model5
▰ Significance: Describes the release rate of drugs from
matrix systems
▰ Equation: Q=KH or Mt/M0 = KH
▰ Or Q=KH t1/2 or Mt/M0 = Kh t1/2
▻ Showing the amount of drug released is proportional to the
square root of time
▻ Q = amount of drug released at time t (in hours)
▻  KH = release constant of Higuchi
▰
▰ Graphical representation: Q vs

▰ Examples: Solid and semi-solid matrices, water

soluble and poorly water soluble drugs, some 14
 2.3 Higuchi Model5
▰ Explanation: Higuchi model is based on following hypotheses
i. The initial amount of drug in the matrix is greater than its solubility (to achieve the saturation of
medium, drug may also get destroyed by First Pass Metabolism, some injectables control the release
of drug, hence, drug must be present in concentration higher than its solubility to achieve therapeutic
level)
ii. Drug diffusion occurs in one dimension only (boundary condition, turbulent flow of medium, etc. may
effect diffusion)
iii. System thickness is greater than drug particle size
iv. Dissolution or matrix swelling is negligible
v. Perfect sink conditions are maintained

▰ This model assumes that the systems are neither surface coated nor that their matrices
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undergo a significant alteration in the presence of water.
 2.4 Hixson–Crowell Model6

Cube root of cumulative amount of drug released

▰ Significance: The area of particles is proportional to the
cube root of its volume
▰ Equation:
▻W0 = initial amount of the drug in the system
▻Wi = amount remaining in the system on time t
▰ 
▻KHC = constant, which relates surface and volume

▰ Graphical representation: cube root of cumulative

amount of drug released vs time
▰ Example: Tablets 16
 2.4 Hixson–Crowell Model6
▰ Explanation: It is considered that dissolution occurs in planes parallel to the surface
of the active agent if the dosage form dimensions decrease proportionally, but with
maintenance of the geometrical characteristics (surface area dependent release i.e.
the release is dependent upon the surface of dosage form exposed to dissolution
medium)

▰ This model assumes that the release rate of drug is limited by drug particles and
dissolution rate and not by diffusion through polymer matrix, hence, is most
commonly applied to tablets
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2.5 Ritger–Peppas and Korsmeyer–
Peppas Model (Power Law)7
▰ Significance: Power law is a more comprehensive semi-empirical equation to describe
drug release from polymeric systems. This model was developed as a semi-empirical
model, establishing the exponential relationship between the release and the time.
▰ Equation: Mt / M∞ = Ktn
▻ Mt / M∞ = fraction of drug released at time t

▻ M ∞ = total amount of drug in dosage form,

▻ Mt = amount of drug released over time t,

▻ K = release rate constant
▻ n = release exponent
▰ Graphical representation: log % (Mt/M∞) vs log t
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▰ Example: polymeric matrix such as hydrogel.
2.5 Ritger–Peppas and Korsmeyer–
Peppas Model (Power Law)7
▰ Once it has been ascertained that the mechanism of drug release is diffusion controlled
from Higuchi plot, then to ascertain the release of drug follows which type of
mechanism, the release data is fitted to model proposed by Korsmeyer and Peppas.

▰ The power law model is useful for the study of drug release from polymeric systems
or modified release dosage forms when the release mechanism is not known or when
more than one type of phenomenon of drug release is involved.

▰ Depending on the value of n that better adjusts to the release profile of an active agent
in a matrix system, it is possible to establish a classification, according to the type of
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observed behavior:
 Release Drug transport Rate as a Release type

Evaluation exponent (n) phenomenon function of time

of
diffusional
release
mechanisms
from
2.5 Ritger–Peppas and Korsmeyer–Peppas Model (Power Law)
polymeric
films

Diffusion release,
0.5 Fickian diffusion t-0.5 square root of time
dependant

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2.5 Ritger–Peppas and Korsmeyer–
Peppas Model (Power Law)

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 2.6 Brazel and Peppas Model8

▰ Significance: In release systems controlled by swelling, the water absorption and

drug release can be described by two-dimensional parameters using the diffusing
number Deborah (De). The number De expresses the relationship between the
▰ 
relaxation time* and diffusion time.
▰ Equation: De =
▻ λ = relaxation time of the polymer
▻ θ = diffusion time of water for a swellable matrix

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2.6 Brazel and Peppas Model8

▰ Explanation: When the swelling process is determined, by relaxation time (De

> > 1) or by diffusion of water (De < < 1), the following process is a function
of time, characterizing a Fickian process. In contrast, when De is near 1, it is
considered that the two processes are occurring simultaneously (Anomalous
transport)

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 2.7 Weibull Model11
▰ Significance: Useful for comparing the drug release profiles of matrix systems. Also
applied to analyze the dissolution and release of drug in different experimental
conditions.
▰ Equation: m = drug fraction accumulated at time t
▻ a = timescale of the process
T = lag time measured as a result of dissolution
process (latency time)
b = type/shape of the curve

b =1 (exponential), b>1 (sigmoid, Fick’s diffusion), b<1 (parabolic, Fick’s diffusion and swelling
controlled transport)
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 3. Model Independent Approaches

Difference Factor (f1)13

▰ The difference factor (f1) defines/measures the percent error between two different
formulations over all time periods and is represented by following equation:

▰ 
▻ Where n = number of samples, Rj and Tj = the percent dissolved of the reference and test
formulations at each time, respectively.

▰ The percent error is zero when the test and reference formulations dissolution profiles
are similar and increases with increase in dissimilarity between them. 25
 3. Model Independent Approaches
▰ Similarity Factor (f2)14
▰ The similarity factor (f2) defines the similarity of dissolution profile of different
formulations by taking log reciprocal square root of sum of errors over all times and is
determined by following equation:

▰ 
Where wj = weight factor, n = number of samples, Rj and Tj = the percent dissolved of the reference and test
formulations at each time, respectively.
▰ This method is more suitable for dissolution profile comparison when more than three
time points are available. The dissolution data is fitted from 0 to 100. 100 means test
and reference formulations are similar and 0 means they are dissimilar. The similar
dissolution profiles must have f1 value close to 0 and f2 value close to 100 26
 Selection of Best Model
▰ The selection of the suitable model in the drug release studies is difficult to ensure the
effectiveness of the study. Criterias for the selection of best suitable models is based
upon the statistical treatments. Determination of coefficient is widely used method to
assess the fit of the model equation. This method also used when the model equation
parameters are same. The best model is the one which have the highest coefficient of
determination R2 (0.9 or above). Similarly other statistical methods like correlation
coefficient (R), Analysis of Variance (ANOVA) and Multivariate analysis of Variance
(MANOVA) are used for the comparison and selection of the suitable models. The
correlation coefficient (R2) values were used to assess whether the release profile
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 4. Case Study15
Application of Mathematical Models in Drug Release Kinetics of Carbidopa and Levodopa ER Tablets

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4. Case Study

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4. Case Study

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4. Case Study

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 5. Conclusion
▰ Study of mathematical modeling is promising which deals with the release
characteristics of dosage forms. Assessment of pattern of release of drug is an
innovative point. The modeling on drug release shows the relationship between drug
dissolution and geometry on drug release patterns mathematically. The drug transport
inside pharmaceutical system and its release sometimes involve multiple steps
provoked by different physical or chemical phenomenon making it difficult, or even
impossible to get a mathematical model describing in the correct way. The fact that
drug delivery system with multilayered tablet has shown promising results in drug
delivery technology and ease of manufacturing is an added advantage to the
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 6. References
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delivery systems. Journal of Controlled Release, 190, 75–81.
2. Davis Yohanes Arifin , Lai Yeng Lee , Chi-hwa Wang ; Mathematical Modeling And Simulation Of Drug Release From Microspheres:
Implications To Drug Delivery Systems ; Advanced Drug Delivery Reviews 58 (2006) 1274–1325.
3. Walters, K. A., & Brain, K. R. (2009). Dermatological formulation and transdermal systems. In K. A. Waletrs (Ed.), Dermatological and
transdermal formulations (pp. 319–400). New York: Informa.
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5. Siepmann, J., & Peppas, N. A. (2012). Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC).
Advanced Drug Delivery Reviews, 64, 163–174.
6. Kosmidis, K., Argyrakis, P., & Macheras, p. (2003). Fractal kinetics in drug release from finite fractal matrices. Journal of Chemical Physics,
119, 6373–6377.
7. Hixson, A. W., & Crowell, J. H. (1931). Dependence of reaction velocity upon surface and agitation: I–Theoretical consideration. Industrial and
Engineering Chemistry, 23, 923–931.
8. O’Hara, T., Dunne, A., Butler, J., & Devane, J. (1998). A review of methods used to compare dissolution profile data. Pharmaceutical Science
and Technology Today, 1, 214–223.
9. Baker, R. W., & Lonsdale, H. S. (1974). Controlled release: mechanisms and rates. In A. C. Taquary, & R. E. Lacey (Eds.), Controlled release of
biologically active agents (pp. 15–71). New York: Plenum.
10. Sibanda, W., Pillay, V., Danckwerts, M. P., Viljoen, A. M., van Vuuren, S., & Khan, R. A. (2004). Experimental design for the formulation and
optimization of novel cross-linked oilispheres developed for in vitro site-specific release of mentha piperita oil. AAPS PharmSciTech, 5, 18.
11. Langenbucher, F. (1972). Linearization of dissolution rate curves by the Weibull distribution. Journal of Pharmacy and Pharmacology, 24, 979
12. Peppas, N. A., & Sahlin, J. J. (1989). A simple equation for the description of solute release. III. Coupling of diffusion and relaxation.
International Journal of Pharmaceutics, 57, 169–172.
13. Araujo, F., das Neves, J., Martins, J. P., Granja, P. L., Santos, H. A., and Sarmento, B. (2017). Functionalized materials for multistage platforms
in the oral delivery of biopharmaceuticals. Progress in Materials Science, 89, 306-344.
14. Costa, P., and Lobo, J. M. S. (2001). Modeling and comparison of dissolution profiles. European Journal of Pharmaceutical Sciences, 13(2),
123-133. 33
15. Gouda R., Baishya H. and Zhao Q. 2017. Application of mathematical models in drug release kinetics of carbidopa and levodopa ER tablets.
Journal of Developing Drugs, 6(2), 1-8.
“ Jazakallahu Feekum

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